This project consists of two related lines of research evaluating 1) the neuroendocrine responses to surgical stress and inflammation, as evidenced by measuring changes in immunoreactive bradykinin (iBK) and beta-endorphin (iB-END), and 2) the analgesic and anti-inflammatory effects of prototype and novel analgesic drugs on altering either the synthesis or the receptor activation of these mediators. Evidence supporting bradykinin's involvement in clinical models of inflammation comes from our finding that blood-borne levels of immunoreactive bradykinin (iBK) are significantly elevated during the surgical removal of impacted third molars. This finding extends last years observations that iBK the significantly elevated in patients with rheumatoid arthritis and in rats with carrageenan-induced inflammation. The potential unity of bradykinin antagonists were evaluated in rats using drugs which either block the synthesis of iBK or which act as receptor antagonists. Prototype drugs representing both pharmacological approaches displayed significant anti-inflammatory activity in the rat carrageenan model of inflammation. This year, we have also continued our research on the pituitary secretion of immunoreactive beta endorphin (iB-END) in response to inflammation. Our results indicate that inflamed tissue from both rat and human samples, contains a peripheral corticotroph-stimulating factor which promotes iB-END release both in cultured pituitary cells and in vivo. Thus, the pituitary-adrenal response to a stressor may be a result of both hypothalamic (i.e., release of CRF) and extra- hypothalamic input, with stressors differing in their activation of these two systems.